During the current grant period we accomplished the monumental task of generating a humanized mouse model for polyarthritis using our HLA-DQ8 transgenic mice. In this proposal we will build this humanized mouse model to obtain all the critical information to understand the mechanism, etiology, and hopefully immunotherapy in this disease model which can be applied to the human disease. By generating additional transgenic mice expressing HLA-DQ genes from RA linked and RA non-linked haplotypes, we will conform a role for DQ polymorphism in the predisposition to the disease. By generating additional transgenic mice expressing HLA-DQ genes from RA linked and RA non-linked haplotypes, we will confirm a role for DQ polymorphism in the predisposition to the disease. In this proposal we will confirm whether HLA-DR2 molecule can protect HLA- DQ8 transgenic mice from collagen-induced arthritis, and will generate additional HLA-DR transgenic mice from RA linked and RA non-linked haplotypes to demonstrate that the polymorphism within the HLA-DRB1 genes determine modulation of collagen-induced arthritis. We will determine the T cell epitopes on human type II collagen using our transgenic mouse model. Similarly, antibodies to specific cyanogen bromide fragments of human type II collagen will be identified after immunization of the HLA-DQ8 mice as well as the other controls with human, bovine, chick, and porcine type II collagen. Next, we will determine the T cell subsets, the cytokine profile, and IgG antibody subtypes in CIA susceptible, non susceptible, and CIA-protected mice to determine the mechanism by which the arthritis is initiated in this mouse model and how they are modulated. We will explore potential immunotherapy in this mouse model and how they are modulated. We will explore potential immunotherapy in this humanized mouse model of arthritis using human type II collagen and the peptides, and antibodies against human class II molecules. Finally, we will try to generate an even better humanized mouse model for arthritis by replacing the mouse CD4 gene with the human CD4 gene in our HLA-DQ and HLA-DR transgenic mice. Thus, we will have a mouse model constituting the tri-molecular complex derived from the HLA-DQ and DR genes, the human CD4 T cells, and the human type II collagen. We believe this model will reveal new clues into the human disease.